Cancer is the second (after cardio-vascular diseases) leading cause of death in the developed world. An enormous research effort of the last decades has produced dramatic advances in understanding mechanisms of transformation, i.e., of the process by which a normal cell becomes cancerous. The pace of discovery has quickened in the last several years with new tools of molecular biology coming to aid, many of which have actually been developed in the effort to understand cancer. Unfortunately, the treatment of cancers has not seen much improvement, and with several notable exceptions, the five-year survival rate has remained about the same throughout this period of several decades--some 50% overall.
In multicellular organisms, division of an individual cell is an event controlled by the needs of the whole organism. While most cells are capable of dividing, or mitosis, they rarely do so if not stimulated to by the conditions of the tissues they form. If an injury is inflicted, for example, the local, as well as the infiltrating cells, may respond by mitosis and tissue regeneration in order to repair the damage. Once the repair is done, the cells return to their quiet existence without proliferation. In some cases, the division of cells is a rule rather than exception. For example, in the bone marrow, cell proliferation continuously provides for blood cells replenishment. The intestinal lining cells also proliferate continuously in order to make up for the loss of the outermost layers caused by in the harsh environment where cells do not last very long. In a healthy individual the steady state is well controlled by local conditions of blood supply, geometrical intercellular relationships, territorial integrity, as well as by systemic factors such as growth factors production, nutrient availability, and the like. The imbalance between cell proliferation and cell death caused by the loss of normal mitotic cycle controls leads to a tumor or neoplasm. If the growth remains local, the tumor is said to be benign, and a complete surgical resection leads to cure. Some tumors, however, possess mechanisms allowing the tumor cells to spread into and proliferate in other tissues. Such tumors are characterized as malignant, and are referred to as cancers. The spread of the tumor cells into other tissues involves the steps of cell separation from the local tumor mass, entry into the blood or lymphatic circulation, transport to another site, entry into that site and continued growth. Treatment of cancers which have spread to various locations, and have formed the secondary tumors, or metastases, is very difficult. In order to succeed, the attack must be selective. Finding selective strategies is the main topic of clinical cancer research efforts. Indeed, the possibility of discovering a successful cancer treatment must be the main motivation of all research on cancer and related aspects of cell biology.
In general, tumors appear to be monoclonal, i.e., all of the tumor cells have descended from a single progenitor cell. Transformation which has made the progenitor cell cancerous is a slow, multiple stage process requiring, in most known cases, a number of specific genetic defects. The genes affected are called oncogenes and the products they encode are called oncoproteins. The changes in DNA sequence may be produced by chemical carcinogens, ionizing radiation, or viral infection, but many other factors play a role in the process. The end effect by which the cell is recognized as tumorous is the apparent lack of proliferation control. To decide whether a cell is transformed, or not, one can make two functional tests: (1) if the cell divides in suspension, i.e., without "anchorage"; or (2) if the cell grows into a tumor in a nude mouse (a mouse with no immune system), the cell most likely is transformed. The discovery of the first oncogene inspired a great deal of optimism based on the hope that perhaps only that single defect needed to be somehow corrected to cure cancer. But tens of oncogens (just over one hundred by now) were identified very quickly and it became clear that cancer was what it has been taken for--a multitude of diseases. Nevertheless, the multitude of diseases that make up cancer all do lead to very similar manifestations. The ultimate common path in the death of the patient keeps the hope alive that there might be a single cure yet.
As of now, the surgical treatment, whenever possible is still the most efficient treatment. If the cancer has not spread from its primary site, the complete resection of the tumor leads to cure of the cancer. If surgery is not possible, or the spread of cancer cells has occurred prior to surgery, chemotherapy may kill some types of cancers. Not all types of cancer are susceptible to chemotherapy, however, and the treatment is, in any case, a balancing game--killing as much of the cancer without killing the patient. The toxic chemicals used for chemotherapy are specific to different phases of the cell cycle, and only a number of cells will be killed by any single dose--some of them cancerous, some of them normal cells that proliferate continuously (most importantly cells in the bone marrow and intestines). Treatment protocols have been developed over years of experimentation and clinical use aimed at combining different drugs in ways to maximize the chances of cancer elimination. Radiation treatment is another possibility, used mostly in conjunction with surgery. In this case, again, the problem is differentiating sufficiently between the normal and cancerous tissue. Even when the cancer is spatially distinct, the methods of radiation delivery available today are not very precise. Asynchronous cell proliferation is a major drawback here as well because cells are not equally susceptible to radiation in different parts of the cycle.
Other physical treatment approaches have been tried and have to a great extent remained experimental--local hyperthermia (produced by ultrasound), for example, had been employed as an adjunct to chemotherapy.
Most promising of the new approaches are those based on using either naturally occurring, or engineered, substances that can interfere with cancer growth and spread: Tumor Necrosis Factor has been identified and tested in native and modified forms; Lymphokine Activated Killer cells have been prepared and used in conjunction with interleukine-2; vaccination against melanoma, which appears to have very characteristic surface markers, is under development; and "magic bullet" drugs; i.e., cytotoxic drugs targeted by the aid of specific antibodies, show a great promise against cancers that display antigens not found on the normal cells. As the details of transformation fill in, new possibilities will certainly open up. Just over one hundred oncogens have been identified. The proteins they encode are found at different locations within the cell, and a troubling possibility exists that many cancer cells may not be identified as such by their surface antigens. Entering the cell in order to intervene, while not impossible, is going to be a lot more difficult than to exert the action on the surface and nothing very efficient has been done even for those types of cancer that do possess strong surface antigens.
Of the existing, clinically accepted and widely practiced anti-cancer treatments, the most relevant to this invention is asparaginase treatment which is used primarily in the combined chemotherapy treatments of the childhood acute leukemia. Anti leukemic effects of asparaginase were discovered by chance in the fifties, understood in the sixties and brought to clinical use in the seventies. The treatment is based on a peculiar property of leukemic cells--they do not produce asparagine, a non-essential amino acid. Unfortunately, when exposed to repeated challenges, these cells adapt and turn on the production of asparagine, thus becoming resistant to any further treatment. The other problem is the antigenicity of the enzyme--injected i.v. or i.m. the enzyme causes immune responses which, in addition to rather serious other side effects, may lead to a fast neutralization of circulating enzyme. In spite of these restrictions, asparaginase is today routinely used in combined protocols for childhood acute lymphocytic leukemia.
The unique approach presented here is based on the most universal of the features of all tumor cells--the property that in fact defines them as tumorous--their propensity to grow and proliferate under conditions where normal cells would not. The basic strategy calls for manipulating systematically those proliferation conditions that can affect the cell cycle, within the physiologically admissible bounds, in such a way as to allow tumor cells to cross those critical cycle check points and expose themselves to the hazards of insufficient essential nutrient supply. The preferred targets are essential amino acids, particularly arginine. Tumor cells demonstrate increased requirements for arginine, as we have shown by in vitro work. This requirement is for non-protein use, most likely for production of polyamines via ornithine, and possibly of nitric oxide. Deprivation of arginine is thus more efficient in killing tumor cells than deprivation of any other essential amino acid. Tryptophan is also of special interest since its presence in the fibrillar proteins of the muscle tissue is very small and therefore the attempt of the body to maintain the normal systemic level is easier to overpower by extracorporeal blood treatment.